synthesis and catalytic functionalization of biologically active indoles

Synthesis of Potential 5-HT 6 Receptor Ligands
Table 1. Pd-catalyzed amination of 5-bromo-3-[2-(diethylamino)ethoxy]indoles.
[a] Isolated yield based on the indole. [b] Reaction conditions: 5bromo-3-[2-(diethylamino)ethoxy]indole
(1 mmol), amine
(1.3 mmol), 2 mol-% Pd(OAc) 2, 4 mol-% ligand L, LiHMDS
(1.3 mmol), solvent: toluene 3 mL, 100 °C, 20 h. [c] Reaction conditions:
5-bromo-3-[2-(diethylamino)ethoxy]indole (1 mmol), amine
(1.5 mmol), 6 mol-% Pd(OAc) 2, 12 mol-% ligand L, Cs 2CO 3
(1.0 mmol), solvent: toluene 3 mL, 100 °C, 20 h.
based on a pharmacophore-framework model for known 5-
HT 6 receptor ligands, which was postulated in 2004 by Holenz
et al. [6] based on a medicinal-chemistry-guided analysis
of reference compounds. Favourable sulfonyl motives came
from a modelling study of Pullagurla et al., including naphthyl,
benzothiophenyl, imidazo[2,1-b]thiazolyl and p-aminophenyl
substituents. [14]
The newly synthesized sulfonylated indoles are listed in
Table 3. Treatment of the respective 5-aminoindole with the
different aryl- and heteroarylsulfonyl chlorides in Et 3Nat
40 °C or in CH 2Cl 2 in the presence of Cs 2CO 3 at room temperature
for 2 h gave the corresponding sulfonylated indole
derivatives 5a–h in general in good yields (Table 3, entries
1–4, 6–7 and 9, 50–98%). An exception is the reaction with
6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (Table 3,
entry 5) which gave a lower yield due to the decreased reactivity
of this sulfonyl chloride. In accordance with the pharmacophore-framework
model for 5-HT 6 receptor ligands
Table 2. Pd-catalyzed hydrogenation.
[a] Isolated yield based on indole derivative. [b] Reaction conditions:
Indole derivative (1 mmol), Pd/C (10%) (200 mg), H 2, 50 bar, room
temp., 8 h in 40 mL of ethanol. [c] Reaction conditions: Indole derivative
(1 mmol), Pd/C (10%) (200 mg), H 2, 5 bar, 60 °C, 3.5 h in
40 mL of ethanol.
Scheme 5. Sulfonylation of 5-amino-3-[2-(diethylamino)ethoxy]indoles
with different sulfonyl chlorides.
the newly prepared compounds in Table 3 possess two
hydrophobic areas and an indole core. Because the receptor-ligand
affinity increases additionally with a free NHgroup
in position 1, we have deprotected compound 5g and
5h to the biologically more active indole derivatives 6a and
6b. We obtained these indole derivatives in high yields up
to 88% (Table 3, entries 8 and 10).
Finally, we studied the sulfonylation of the 3-siloxy-protected
5-aminoindoles 7a–e [13a] to give 8a–i (Scheme 6).
Scheme 6. Sulfonylation of 5-amino-3-(silyloxy)indoles with different
sulfonyl chlorides.
Eur. J. Org. Chem. 2008, 5425–5435 © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 5427